A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells
Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that i...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2015-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/09384 |
| _version_ | 1811227430167248896 |
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| author | Heidi Hehnly David Canton Paula Bucko Lorene K Langeberg Leah Ogier Irwin Gelman L Fernando Santana Linda Wordeman John D Scott |
| author_facet | Heidi Hehnly David Canton Paula Bucko Lorene K Langeberg Leah Ogier Irwin Gelman L Fernando Santana Linda Wordeman John D Scott |
| author_sort | Heidi Hehnly |
| collection | DOAJ |
| description | Correct orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin−/− mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division. |
| first_indexed | 2024-04-12T09:42:25Z |
| format | Article |
| id | doaj.art-7a011613427d4eeaae2a859ad312900d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:42:25Z |
| publishDate | 2015-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-7a011613427d4eeaae2a859ad312900d2022-12-22T03:38:03ZengeLife Sciences Publications LtdeLife2050-084X2015-09-01410.7554/eLife.09384A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cellsHeidi Hehnly0David Canton1Paula Bucko2Lorene K Langeberg3Leah Ogier4Irwin Gelman5L Fernando Santana6Linda Wordeman7John D Scott8Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United States; Department of Cell and Developmental Biology, State University of New York Upstate Medical University, Syracuse, United StatesDepartment of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United StatesDepartment of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United StatesDepartment of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United StatesDepartment of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United StatesDepartment of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, United StatesDepartment of Physiology and Biophysics, University of Washington, Seattle, United StatesDepartment of Physiology and Biophysics, University of Washington, Seattle, United StatesDepartment of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, United StatesCorrect orientation of the mitotic spindle in stem cells underlies organogenesis. Spindle abnormalities correlate with cancer progression in germ line-derived tumors. We discover a macromolecular complex between the scaffolding protein Gravin/AKAP12 and the mitotic kinases, Aurora A and Plk1, that is down regulated in human seminoma. Depletion of Gravin correlates with an increased mitotic index and disorganization of seminiferous tubules. Biochemical, super-resolution imaging, and enzymology approaches establish that this Gravin scaffold accumulates at the mother spindle pole during metaphase. Manipulating elements of the Gravin-Aurora A-Plk1 axis prompts mitotic delay and prevents appropriate assembly of astral microtubules to promote spindle misorientation. These pathological responses are conserved in seminiferous tubules from Gravin−/− mice where an overabundance of Oct3/4 positive germ line stem cells displays randomized orientation of mitotic spindles. Thus, we propose that Gravin-mediated recruitment of Aurora A and Plk1 to the mother (oldest) spindle pole contributes to the fidelity of symmetric cell division.https://elifesciences.org/articles/09384protein kinasesignal transductioncell regulationmitotic spindletesticular cancer |
| spellingShingle | Heidi Hehnly David Canton Paula Bucko Lorene K Langeberg Leah Ogier Irwin Gelman L Fernando Santana Linda Wordeman John D Scott A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells eLife protein kinase signal transduction cell regulation mitotic spindle testicular cancer |
| title | A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells |
| title_full | A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells |
| title_fullStr | A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells |
| title_full_unstemmed | A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells |
| title_short | A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells |
| title_sort | mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells |
| topic | protein kinase signal transduction cell regulation mitotic spindle testicular cancer |
| url | https://elifesciences.org/articles/09384 |
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